The University of California, San Francisco (UCSF) conducts clinical trials in a wide range of autoimmune diseases. This proposal focuses on three of these diseases (SLE, MS, and IDDM), and presents detailed descriptions of two potential clinical trials that demonstrate our interests and our ability to develop collaborative multicenter clinical trials for patients with autoimmune diseases. The two proposed clinical trials are: Protocol 1: Treatment of lupus nephritis with CTLA4Ig, a fusion protein that inhibits T cell costimulation via the CD28 pathway. This trial represents the culmination of a comprehensive bench-to-bedside research program conducted at UCSF by the PI of the Clinical Center and the PI of Project 2 in this application. The proposed trial will determine: (i) whether CTLA4Ig augments the benefit of cyclophosphamide (CTX) therapy in patients with lupus nephritis; (ii) whether CTLA4Ig can minimize the duration of therapy with CTX; (iii) whether combined therapy with CTX and CTLA4Ig can eliminate the need for maintenance therapy (induce 'tolerance'); and (iv) whether CTLA4Ig is better tolerated/safer than CTX. Protocol 2: Treatment with atorvastatin to prevent progression to MS after a clinically isolated first attack of CNS demyelination. This trial also represents a true bench-to-bedside collaboration among basic and clinical scientists involved in this application. It arose from studies by Dr. Scott Zamvil at UCSF, demonstrating that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') can prevent or reverse paralysis in murine models for MS. The proposed trial will determine whether atorvastatin can prevent progression to MS in patients at high risk for the developing the disease. Although it is not represented in this application by a detailed protocol, the Diabetes program at UCSF also has a very strong clinical trials component. The short-term goal of our clinical trials program in diabetes is to extend recent studies of anti-CD3 therapy to determine the potential of this approach to treat early IDDM and/or to prevent IDDM in people at high risk for the disease. We also are conducting trials to examine new strategies to facilitate islet transplantation. In addition to our studies in SLE, MS, and IDDM, investigators affiliated with our Center are currently conducting clinical trials in numerous other autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Sjogren syndrome, scleroderma, and Wegener's granulomatosis. This breadth of interests and experience at UCSF provides evidence of our ability to contribute across a broad range of potential ACE trials.